DNA-dependent protein kinase drives prostate cancer progression through transcriptional regulation of the Wnt signaling pathway

Vishal Kothari, Jonathan F. Goodwin, Shuang G. Zhao, Justin M. Drake, Yi Yin, S. Laura Chang, Joseph R. Evans, Kari Wilder-Romans, Kristina Gabbara, Emanuela Dylgjeri, Jonathan Chou, Grace Sun, Scott A. Tomlins, Rohit Mehra, Kristen Hege, Ellen H. Filvaroff, Edward M. Schaeffer, R. Jeffrey Karnes, David A. Quigley, Dana E. RathkopfHousheng H. He, Corey Speers, Daniel E. Spratt, Luke A. Gilbert, Alan Ashworth, Arul M. Chinnaiyan, Ganesh V. Raj, Karen E. Knudsen, Felix Y. Feng

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Purpose: Protein kinases are known to play a prominent role in oncogenic progression across multiple cancer subtypes, yet their role in prostate cancer progression remains underexplored. The purpose of this study was to identify kinases that drive prostate cancer progression. Experimental Design: To discover kinases that drive prostate cancer progression, we investigated the association between gene expression of all known kinases and longterm clinical outcomes in tumor samples from 545 patients with high-risk disease. We evaluated the impact of genetic and pharmacologic inhibition of the most significant kinase associated with metastatic progression in vitro and in vivo. Results: DNA-dependent protein kinase (DNAPK) was identified as the most significant kinase associated with metastatic progression in high-risk prostate cancer. Inhibition of DNAPK suppressed the growth of both AR-dependent and AR-independent prostate cancer cells. Gene set enrichment analysis nominated Wnt as the top pathway associated with DNAPK. We found that DNAPK interacts with the Wnt transcription factor LEF1 and is critical for LEF1-mediated transcription. Conclusions: Our data show that DNAPK drives prostate cancer progression through transcriptional regulation ofWnt signaling and is an attractive therapeutic target in aggressive prostate cancer.

Original languageEnglish (US)
Pages (from-to)5608-5622
Number of pages15
JournalClinical Cancer Research
Volume25
Issue number18
DOIs
StatePublished - Sep 15 2019

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DNA-Activated Protein Kinase
Wnt Signaling Pathway
Prostatic Neoplasms
Phosphotransferases
Wnt Proteins
Protein Kinases
Neoplasms
Research Design
Transcription Factors
Gene Expression
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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DNA-dependent protein kinase drives prostate cancer progression through transcriptional regulation of the Wnt signaling pathway. / Kothari, Vishal; Goodwin, Jonathan F.; Zhao, Shuang G.; Drake, Justin M.; Yin, Yi; Chang, S. Laura; Evans, Joseph R.; Wilder-Romans, Kari; Gabbara, Kristina; Dylgjeri, Emanuela; Chou, Jonathan; Sun, Grace; Tomlins, Scott A.; Mehra, Rohit; Hege, Kristen; Filvaroff, Ellen H.; Schaeffer, Edward M.; Karnes, R. Jeffrey; Quigley, David A.; Rathkopf, Dana E.; He, Housheng H.; Speers, Corey; Spratt, Daniel E.; Gilbert, Luke A.; Ashworth, Alan; Chinnaiyan, Arul M.; Raj, Ganesh V.; Knudsen, Karen E.; Feng, Felix Y.

In: Clinical Cancer Research, Vol. 25, No. 18, 15.09.2019, p. 5608-5622.

Research output: Contribution to journalArticle

Kothari, V, Goodwin, JF, Zhao, SG, Drake, JM, Yin, Y, Chang, SL, Evans, JR, Wilder-Romans, K, Gabbara, K, Dylgjeri, E, Chou, J, Sun, G, Tomlins, SA, Mehra, R, Hege, K, Filvaroff, EH, Schaeffer, EM, Karnes, RJ, Quigley, DA, Rathkopf, DE, He, HH, Speers, C, Spratt, DE, Gilbert, LA, Ashworth, A, Chinnaiyan, AM, Raj, GV, Knudsen, KE & Feng, FY 2019, 'DNA-dependent protein kinase drives prostate cancer progression through transcriptional regulation of the Wnt signaling pathway', Clinical Cancer Research, vol. 25, no. 18, pp. 5608-5622. https://doi.org/10.1158/1078-0432.CCR-18-2387
Kothari, Vishal ; Goodwin, Jonathan F. ; Zhao, Shuang G. ; Drake, Justin M. ; Yin, Yi ; Chang, S. Laura ; Evans, Joseph R. ; Wilder-Romans, Kari ; Gabbara, Kristina ; Dylgjeri, Emanuela ; Chou, Jonathan ; Sun, Grace ; Tomlins, Scott A. ; Mehra, Rohit ; Hege, Kristen ; Filvaroff, Ellen H. ; Schaeffer, Edward M. ; Karnes, R. Jeffrey ; Quigley, David A. ; Rathkopf, Dana E. ; He, Housheng H. ; Speers, Corey ; Spratt, Daniel E. ; Gilbert, Luke A. ; Ashworth, Alan ; Chinnaiyan, Arul M. ; Raj, Ganesh V. ; Knudsen, Karen E. ; Feng, Felix Y. / DNA-dependent protein kinase drives prostate cancer progression through transcriptional regulation of the Wnt signaling pathway. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 18. pp. 5608-5622.
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abstract = "Purpose: Protein kinases are known to play a prominent role in oncogenic progression across multiple cancer subtypes, yet their role in prostate cancer progression remains underexplored. The purpose of this study was to identify kinases that drive prostate cancer progression. Experimental Design: To discover kinases that drive prostate cancer progression, we investigated the association between gene expression of all known kinases and longterm clinical outcomes in tumor samples from 545 patients with high-risk disease. We evaluated the impact of genetic and pharmacologic inhibition of the most significant kinase associated with metastatic progression in vitro and in vivo. Results: DNA-dependent protein kinase (DNAPK) was identified as the most significant kinase associated with metastatic progression in high-risk prostate cancer. Inhibition of DNAPK suppressed the growth of both AR-dependent and AR-independent prostate cancer cells. Gene set enrichment analysis nominated Wnt as the top pathway associated with DNAPK. We found that DNAPK interacts with the Wnt transcription factor LEF1 and is critical for LEF1-mediated transcription. Conclusions: Our data show that DNAPK drives prostate cancer progression through transcriptional regulation ofWnt signaling and is an attractive therapeutic target in aggressive prostate cancer.",
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T1 - DNA-dependent protein kinase drives prostate cancer progression through transcriptional regulation of the Wnt signaling pathway

AU - Kothari, Vishal

AU - Goodwin, Jonathan F.

AU - Zhao, Shuang G.

AU - Drake, Justin M.

AU - Yin, Yi

AU - Chang, S. Laura

AU - Evans, Joseph R.

AU - Wilder-Romans, Kari

AU - Gabbara, Kristina

AU - Dylgjeri, Emanuela

AU - Chou, Jonathan

AU - Sun, Grace

AU - Tomlins, Scott A.

AU - Mehra, Rohit

AU - Hege, Kristen

AU - Filvaroff, Ellen H.

AU - Schaeffer, Edward M.

AU - Karnes, R. Jeffrey

AU - Quigley, David A.

AU - Rathkopf, Dana E.

AU - He, Housheng H.

AU - Speers, Corey

AU - Spratt, Daniel E.

AU - Gilbert, Luke A.

AU - Ashworth, Alan

AU - Chinnaiyan, Arul M.

AU - Raj, Ganesh V.

AU - Knudsen, Karen E.

AU - Feng, Felix Y.

PY - 2019/9/15

Y1 - 2019/9/15

N2 - Purpose: Protein kinases are known to play a prominent role in oncogenic progression across multiple cancer subtypes, yet their role in prostate cancer progression remains underexplored. The purpose of this study was to identify kinases that drive prostate cancer progression. Experimental Design: To discover kinases that drive prostate cancer progression, we investigated the association between gene expression of all known kinases and longterm clinical outcomes in tumor samples from 545 patients with high-risk disease. We evaluated the impact of genetic and pharmacologic inhibition of the most significant kinase associated with metastatic progression in vitro and in vivo. Results: DNA-dependent protein kinase (DNAPK) was identified as the most significant kinase associated with metastatic progression in high-risk prostate cancer. Inhibition of DNAPK suppressed the growth of both AR-dependent and AR-independent prostate cancer cells. Gene set enrichment analysis nominated Wnt as the top pathway associated with DNAPK. We found that DNAPK interacts with the Wnt transcription factor LEF1 and is critical for LEF1-mediated transcription. Conclusions: Our data show that DNAPK drives prostate cancer progression through transcriptional regulation ofWnt signaling and is an attractive therapeutic target in aggressive prostate cancer.

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